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Los canales de potasio KCNJ3 y KCNJ5 mutados como nuevos objetivos moleculares en las arritmias y la fibrilación
Noriaki Yamada1, Yoshihiro Asano1, Masashi Fujita2
1Departments of Cardiovascular Medicine (N.Y., Y.A., A.T., H. Kioka, Y.M., H.S., Y.S.), Osaka University Graduate School of Medicine, Suita, Japan.
Circulation
|February 16, 2019
Resumen
El análisis genético identificó una nueva mutación KCNJ3 que causa bradiarritmias hereditarias. Un compuesto dirigido mejoró efectivamente la frecuencia cardíaca en un modelo de pez cebra, lo que sugiere un nuevo enfoque terapéutico para la bradicardia.
Área de la Ciencia:
- Cardiología
- La genética
- Farmacología
Sus antecedentes:
- La bradiarritmia, a menudo adquirida, puede tener causas genéticas.
- El tratamiento actual para la bradiarritmia sintomática implica la implantación invasiva de marcapasos.
- Se necesitan nuevos objetivos moleculares terapéuticos para mejorar los resultados de la bradiarritmia.
Objetivo del estudio:
- Investigar una familia con bradiarritmias autosómicas dominantes.
- Identificar la mutación genética causante.
- Explorar estrategias terapéuticas dirigidas a los mecanismos moleculares identificados.
Principales métodos:
- Secuenciación de exomas enteros basados en la familia y análisis de vínculos en todo el genoma.
- Caracterización in vitro de los mecanismos relacionados con las mutaciones.
- Generación de un modelo de pez cebra transgénico y evaluación de un compuesto objetivo.
Principales resultados:
- Se identificó una nueva mutación heterocigótica de KCNJ3 (p.N83H) como una causa de bradiarritmias hereditarias.
- La mutación resultó en una ganancia de función en el canal de potasio activado por acetilcolina (IKACh).
- Un bloqueador selectivo del canal IKACh (NIP-151) reprimió el aumento de la corriente y mejoró los fenotipos de bradiarritmia en peces cebra mutantes.
Conclusiones:
- El canal IKACh está implicado en la fisiopatología de la bradiarritmia y la fibrilación auricular.
- La mutación de ganancia de función de KCNJ3 p.N83H puede ser atacada por NIP-151.
- El canal I< sub>KACh representa un objetivo farmacológico potencial para los pacientes con bradiarritmia con mutaciones específicas de ganancia de función.
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